期刊
FASEB JOURNAL
卷 24, 期 12, 页码 5113-5123出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.10-166272
关键词
nicotinic; alpha 6; Conus; hydroxyproline; hippocampus
资金
- Kirschstein-National Research Service Award [DA 016835]
- National Institutes of Health [DA017173, MH53631, GM48677]
- Institut Pasteur
- ANR
- European Union [HEALTH-F2-2008-202088]
- Centre National de la Recherche Scientifique
- Agence Nationale de la Recherche Neurologie
- European Commission
alpha 6* (asterisk indicates the presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) are broadly implicated in catecholamine-dependent disorders that involve attention, motor movement, and nicotine self-administration. Different molecular forms of alpha 6 nAChRs mediate catecholamine release, but receptor differentiation is greatly hampered by a paucity of subtype selective ligands. alpha-Conotoxins are nAChR-targeted peptides used by Conus species to incapacitate prey. We hypothesized that distinct conotoxin-binding kinetics could be exploited to develop a series of selective probes to enable study of native receptor subtypes. Proline6 of alpha-conotoxin BuIA was found to be critical for nAChR selectivity; substitution of proline6 with 4-hydroyx-proline increased the IC(50) by 2800-fold at alpha 6/alpha 3 beta 2 beta 3 but only by 6-fold at alpha 6/alpha 3 beta 4 nAChRs (to 1300 and 12 nM, respectively). We used conotoxin probes together with subunit-null mice to interrogate nAChR subtypes that modulate hippocampal norepinephrine release. Release was abolished in alpha 6-null mutant mice. alpha-Conotoxin BuIA[T5A;P6O] partially blocked norepinephrine release in wild-type controls but failed to block release in beta 4(-/-) mice. In contrast, BuIA[T5A;P6O] failed to block dopamine release in the wild-type striatum known to contain alpha 6 beta 2* nAChRs. BuIA[T5A;P6O] is a novel ligand for distinguishing between closely related alpha 6* nAChRs; alpha 6 beta 4* nAChRs modulate norepinephrine release in hippocampus but not dopamine release in striatum.-Azam, L., Maskos, U., Changeux, J.-P., Dowell, C. D., Christensen, S., De Biasi, M., McIntosh, J. M. alpha-Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between alpha 6 beta 4 and alpha 6 beta 2 nAChRs and blocks nicotine-stimulated norepinephrine release. FASEB J. 24, 5113-5123 (2010). www.fasebj.org
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据